Bridging Spinal networks: Novel 3D substrates as neural implantable interfaces

In modern neuroscience, significant progress in developing structural scaffolds integrated with the brain is provided by the increasing use of nanomaterials. We show that a multiwalled carbon nanotube self-standing framework, consisting of a three-dimensional (3D) mesh of interconnected, conductive, pure carbon nanotubes, can guide the formation of neural webs in vitro where the spontaneous regrowth of neurite bundles is molded into a dense random net. This morphology of the fiber regrowth shaped by the 3D structure supports the successful reconnection of segregated spinal cord segments.We further observed in vivo the adaptability of these 3D devices in a healthy physiological environment. Our study shows that 3D artificial scaffolds may drive local rewiring in vitro and hold great potential for the development of future in vivo interfaces.Neural implants in past decades have offered themselves as a promising tool in finding answers for spinal cord injury and yet no practical treatment is available. Glial barrier and functional deficits are major challenges needed to overcome. Here, we have used a unique scaffold fabricated from 3D multiwalled carbon nanotube fibers (CNF) as a neural implant. We investigated long term in vivo effects of this material implanted in L1 hemisection lesione. Functional locomotor recovery measured by BBB rating scale and ladder rung test demonstrated improvement starting from 24 h post-injury over a course of 8 weeks. Footprint analysis revealed early onset of plantar placement in CNF-implanted animals. Tissue reaction to the implant quantified as GFAP and Iba 1-positive area was limited and invasion of neural processes within the implanted scaffold suggests use of carbon nanofibers as a safe and neuron-friendly scaffold

Functional rewiring across spinal injuries via biomimetic nanofiber scaffolds

The regrowth of severed axons is fundamental to reestablish motor control after spinal-cord injury (SCI). Ongoing efforts to promote axonal regeneration after SCI have involved multiple strategies that have been only partially successful. Our study introduces an artificial carbon-nanotube based scaffold that, once implanted in SCI rats, improves motor function recovery. Confocal microscopy analysis plus fiber tracking by magnetic resonance imaging and neurotracer labeling of long-distance corticospinal axons suggest that recovery might be partly attributable to successful crossing of the lesion site by regenerating fibers. Since manipulating SCI microenvironment properties, such as mechanical and electrical ones, may promote biological responses, we propose this artificial scaffold as a prototype to exploit the physics governing spinal regenerative plasticity

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Nanostructures to Potentiate Axon Navigation and Regrowth in the Damaged Central Nervous Tissue

Neural interfaces as prosthetic devices are engineered in order to achieve neural recording and stimulation, to promote neural regeneration and to assist therapeutic delivery of bioactive molecules. By tailoring the interface architecture with nanoscale geometries, it is possible to mimic topographical cues able to adapt neuronal growth and redirect neurite navigation to a functional recovery. In this chapter, we present an overview of nano-dimensional strategies focusing on the new generation of artificial implantable scaffolds that can provide potential opportunities in brain and spinal cord healing. We strive to discuss how miniaturization of tools and prostheses at the nanoscale will help exploring the central nervous system (CNS) at subcellular scales to exploit artificial devices adaptation to neuronal biology and functions. Finally, some of the key advancements and hurdles currently emerging in the use of such artificial nanodevices in vitro and in vivo are discussed

Ageing ovaries and endometrium in PCOS

Objective: to measure the outcome of age on ovarian and uterine morphology in women with primary infertility due to polycystic ovarian syndrome (PCOS) Materials and Methods: It was an observational cross sectional study. Two hundred primary infertile women with PCOs were subdivided into age groups (years) 20-30 (group I) and 31- 40 (group II). The ovarian volume (OV), follicles count (FC) and size (FS), uterine area (UA) and endometrial thickness (Endo) were determined by trans- abdominal (TAS) and trans -vaginal scan (TVS) using the ultrasound machine. Unpaired t-test was applied to evaluate the result Results: Comparison between group I and group II was made to evaluate the outcome. A significant raise was noted in the uterine morphology of group II. The UA was 89.99±5.83 v/s 119.0±23.33 (0.001) and endometrial thickness was 0.48±0.11 v/s 0.59±0.13 (0.001). A significant decline was noted in the ovarian morphology of group II; the OV (TAS) was 15.36± 2.56 v/s 10.57±12 (0.001) and TVS showed 15.74±2.23 v/s 10.37±1.08 (0.001). The FC was 14.05±1.56 v/s 12.47±0.89 (0.022) and FS was 9.45±7.98 v/s 4.33±5.88 (0.00). Conclusion: The OV, FC and FS (ovarian morphology) variables decreases in the elder infertile group with PCOs but the uterine morphology variables showed an increase in area with thickening of endometrium in the elder group

Nanostructures to Engineer 3D Neural-Interfaces: Directing Axonal Navigation toward Successful Bridging of Spinal Segments

Neural interfaces are the core of prosthetic devices, such as implantable stimulating electrodes or brain–machine interfaces, and are increasingly designed for assisting rehabilitation and for promoting neural plasticity. Thus, beyond the classical neuroprosthetic concept of stimulating and/or recording devices, modern technology is pursuing toward ideal bio/electrode interfaces with improved adaptability to the brain tissue. Advances in material research are crucial in these efforts and new developments are drawing from engineering and neural interface technologies. Here, a microporous, self‐standing, 3D interface made of polydimethylsiloxane (PDMS) implemented at the interfacing surfaces with novel conductive nanotopographies (carbon nanotubes) is exploited. The scaffold porosity is characterized by 3D X‐ray microtomography. These structures are used to interface axons regenerated from cultured spinal explants and it is shown that engineering PDMS 3D interfaces with carbon nanotubes effectively changes the efficacy of regenerating fibers to target and reconnect segregated explant pairs. An improved electrophysiological performance is shown when the spinal tissue is interfaced to PDMS enriched by carbon nanotubes that may favor the use of our substrates as regenerative interfaces. The materials are implanted in the rat brain and a limited tissue reaction surrounding the implants at 2, 4, and 8 weeks from surgery is reported